1. Field of the Invention
The present invention relates generally to treatment or prevention of symptoms of hormonal variation, such as hot flashes, night sweats, and insomnia.
2. Background Art
Hot flashes (also called vasomotor flashes) are the most common symptoms experienced by women who are perimenopausal or postmenopausal. A hot flash is a sudden sensation of warmth, which is usually accompanied by skin reddening, perspiration, palpitation, anxiety, irritability, and even panic, and night sweats. A chill may follow a hot flash because of a subsequent drop in core temperature. Hot flashes vary: they can be several times a week or once per hour, they can be characterized by mild warmth to profuse sweating, and they can last from several seconds to 60 minutes. Such symptoms can disrupt sleep and work and interfere with quality of life.
Almost 60-70% of postmenopausal women have hot flashes, and approximately 10-20% of all postmenopausal women will report intolerable symptoms, including hot flashes. Some women may suffer from these symptoms for up to 15 years (Kronenberg F. “Hot flashes: epidemiology and physiology,” Ann. N.Y. Acad. Sci., 592:52-86(1990)). Thus, the identification and proper management of menopausal symptoms are crucial to maintaining a woman's quality of life.
Typical hot flashes occur with sudden onsets of sensation of warmth in the chest, which then spreads upward to involve the neck and face. Hot flashes can last from a few seconds to several minutes. However, the severity of the sensations vary greatly both from time to time in the same woman and from woman to woman. Hot flashes may be accompanied by dizziness, nausea, headaches, palpitations, profuse sweating and night sweats. How often a woman experiences hot flashes also varies, ranging from many times a day to once a week or less. Such symptoms can disrupt sleep and work and interfere with quality of life. In some women, hot flashes are provoked by several factors such as hot weather, stress, eating, or drinking alcohol.
Although the pathophysiology of hot flashes is not completely understood, it has been postulated that hot flashes result from a transient lowering of the hypothalamic temperature regulatory set point (Steams et al., “Hot flushes,” Lancet, 360:1851-1861 (2002)). Because of the temporal relation between changes in sexual hormone concentrations and the onset of hot flashes, it is believed that such symptoms result from declining estrogen levels or increased gonadotropin concentrations. Thus, hot flashes occur commonly in menopausal women, but also in women taking anti-estrogen drugs, such as tamoxifen. Men on androgen deprivation treatment may also experience such symptoms.
Although estrogen replacement therapy can effectively minimize or prevent hot flashes in women, many women are concerned about potential risks of hormone replacement therapy. This is especially true for women who suffer from breast cancer or have a family history of breast cancer, and/or a history of clotting disorder (Col et al., “Patient-specific decisions about hormone replacement therapy in postmenopausal women,” JAMA, 277; 1140-1147(1997); Gail et al., “The menopause,” Lancet, 353:571-580 (1999)).
Various non-hormonal agents have been tested as well, such as clonidine. Clonidine is a centrally-acting α2 adrenergic receptor agonist. It selectively stimulates receptors in the brain that monitor catecholamine levels in the blood. These receptors close a negative feedback loop that begins with descending sympathetic nerves from the brain that control the production of catecholamines (e.g., epinephrine, also known as adrenaline, and norepinephrine) in the adrenal medulla. By tricking the brain into believing that catecholamine levels are higher than they really are, clonidine causes the brain to reduce its signals to the adrenal medulla, leading to lower catecholamine production. The result is a lowered heart rate and blood pressure. In randomized clinical trials, clonidine was shown to be moderately more efficacious than placebo (Goldberg et al., “Transdermal clonidine for ameliorating tamoxifen-induced hot flashes,” J. Clin. Oncol., 12:155-158 (1994); Pandya et al., “Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study,” Ann Intern Med. 132:788-793 (2000)), but adverse effects are common, including dry mouth, dizziness, and blurred vision.
Recent randomized clinical trials also confirmed that some selective serotonin-reuptake inhibitors (SSRI), such as venlafaxine and paroxetine, are more effective than placebo in minimizing the occurrence and severity of hot flashes (Loprinzi et al., “Venlafaxine in management of hot flashes in survivors of breast cancer: a randomized controlled trial,” Lancet 356:2059-2063 (2000); Stearns et al., “Paroxetine controlled release in the treatment of menopausal hot flashes: A randomized controlled trial,” JAMA 289:2827-2834 (2003)). However, adverse effects with SSRIs are moderate, including headache, agitation, tremor, sedation, and sexual dysfunction.
Given the risks of estrogen replacement therapy and marginal benefits of current non-hormonal treatments, there is a continued need for alternative methods or drugs for treating or preventing symptoms associated with menopause, including hot flashes.